Over the past decade, dihydropyridine calcium antagonists or calcium channel blockers have become widely known therapeutic agents having vasodilator properties which can be used as antihypertensives and coronary dilator agents. These compounds inhibit the entry of calcium into cells, or its mobilization from intracellular stores. More recently, it has been found that small structural modifications of these known compounds produce dihydropyridines with effects diametrically opposed to those of the calcium channel blockers. Dihydropyridines such as Bay K8644 and CGP 28392 (FIG. 1) promote an influx of calcium ions into cells, thereby producing positive inotropic and vasoconstrictor effects. Bay K8644 is more than ten times as potent as CGP 28392 as a calcium agonist. However, Bay K8644 is not useful as a cardiotonic because of its coronary vasoconstricting properties. Therefore it is only useful as a pharmacological tool to ascertain the function of calcium entry blockers. ##STR1##
Representative of the art in the field of dihydropyridine calcium agonists are U.S. Pat. No. 4,248,873 (Bossert et al.), issued Feb. 3, 1981; European Patent Application 0071819 published Feb. 16, 1983 by Boshagen et al.; and U.S. Pat. No. 4,537,881 (Franckowiak et al.), issued Aug. 27, 1985. Literature references include M. Schram, et al., Nature 303:535 (1983); M. Schram, et al., Arzneim-Forsch. 33:1268 (1983); P. Erne, et al., Biochem. Biophys. Res. Commun. 118:842 (1984). Dihydropyridine calcium agonists which contain an amino group in the 2-position are described in U.S. Pat. No. 4,532,248 (Boshagen et al.), issued Jul. 30, 1985.
Combining calcium agonist properties and alpha.sub.1 -adrenergic blocking properties in a single molecular structure provides a new and attractive approach for the treatment of congestive heart failure. The combination of these two types of activities affords a novel class of cardiotonics which have cardiac stimulatory effects in combination with pronounced vasodilator properties. The detrimental vasoconstricting properties which are normally associated with dihydropyridine calcium agonists are minimized by the alpha.sub.1 -adrenergic blocking properties which cause dilation of the peripheral vasculature. Applicants are not aware of any references that describe this combination of properties in a single compound, other than co-assigned U.S. Pat. No. 4,868,181 (Johnson et al.) issued Sep. 19, 1989.